Gas–liquid tubular continuous-flow Pd-catalysed aminocarbonylation process for scalable synthesis of carboxamides

Abstract

Herein we describe an efficient continuous flow process that integrates a custom-designed gas input control system, coupled with a tubular reactor for Pd-catalysed aminocarbonylation, which is able to produce carboxamides in multigram scale, using iodoalkenes and iodoarenes as substrates, CO as the carbonyl source and biologically relevant amines as nucleophiles. Under moderate reaction conditions (pressure ≤ 3 bar and temperature ≤ 100 °C), we synthesised an array of monocarboxamides, namely steroids, indole, and pyridine derivatives (including a lazabemide analogue) with remarkable chemoselectivity, achieving a noteworthy productivity of up to 21 g per day.